Large‐Scale Synthesis of Enantiopure Molecular Cages: Chiroptical and Recognition Properties

A convenient and efficient gram‐scale synthesis for enantiopure hemicryptophane–tren (tren=tris(2‐aminoethyl)amine) derivatives has been developed. The four‐step synthesis is based on the optical resolution of a key intermediate, cyclotriveratrylene, for which the energy barrier for racemization has been measured to ensure that no racemization occurs during the two last steps of the synthetic pathway. The assignments of the absolute configurations have been performed by electronic circular dichroism and the enantiopurity was determined by NMR spectroscopy in the presence of enantiopure camphor sulfonic acid. To highlight the interest of such compounds, the recognition of norephedrine neurotransmitter was investigated and showed a remarkable enantioselectivity towards the C₃ symmetrical hosts. Finally, this highly modular synthetic pathway was used to provide eight enantiopure hemicryptophanes with different sizes, shapes, and functionalities. These results underline the high potential of this approach, which could lead to many applications in chiral recognition or asymmetric supramolecular catalysis.     

Poly(trimethylene carbonate)/Poly(malic acid) Amphiphilic Diblock Copolymers as Biocompatible Nanoparticles

Amphiphilic polycarbonate–poly(hydroxyalkanoate) diblock copolymers, namely, poly(trimethylene carbonate) (PTMC)‐b‐poly(β‐malic acid) (PMLA), are reported for the first time. The synthetic strategy relies on commercially available catalysts and initiator. The controlled ring‐opening polymerization (ROP) of trimethylene carbonate (TMC) catalyzed by the organic guanidine base 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD), associated with iPrOH as an initiator, provided iPrO?PTMC?OH, which served as a macroinitiator in the controlled ROP of benzyl β‐malolactonate (MLABe) catalyzed by the neodymium triflate salt (Nd(OTf)₃). The resulting hydrophobic iPrO?PTMC‐b‐PMLABe?OH copolymers were then hydrogenolyzed into the parent iPrO?PTMC‐b‐PMLA?OH copolymers. A range of well‐defined copolymers, featuring different sizes of segments (M_n,NMR up to 9300 g mol^?1; Ð_M=1.28–1.40), were thus isolated in gram quantities, as evidenced by NMR spectroscopy, size exclusion chromatography, thermogravimetric analysis, differential scanning calorimetry, and contact angle analyses. Subsequently, PTMC‐b‐PMLA copolymers with different hydrophilic weight fractions (11–75 %) self‐assembled in phosphate‐buffered saline upon nanoprecipitation into well‐defined nano‐objects with D_h=61–176 nm, a polydispersity index <0.25, and a negative surface charge, as characterized by dynamic light scattering and zeta‐potential analyses. In addition, these nanoparticles demonstrated no significant effect on cell viability at low concentrations, and a very low cytotoxicity at high concentrations only for PTMC‐b‐PMLA copolymers exhibiting hydrophilic fractions over 47 %, thus illustrating the potential of these copolymers as promising nanoparticles.     

(NHC)AuI]-catalyzed formation of conjugated enones and enals: an experimental and computational study

The [(NHC)AuI]-catalyzed (NHC=N-heterocyclic carbene) formation of alpha,beta-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60 degrees C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF6 and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/AgSbF6 in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and SN2' addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF6] and H2O, instead of cationic [(NHC)AuSbF6] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the C[triple chemical bond]C bond leading to the formation of a gold-allenolate is proposed.     

Investigation into the factors affecting accuracy of mass measurements on a time-of-flight mass spectrometer using Design of Experiment

The results of an investigation of the parameters which have the most significant effect on the accuracy of mass measurements on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (q-oaToF) are reported. The influence of eight factors is investigated: ion abundances of reference and analyte compounds, mass difference between analyte and reference compounds, quality of calibration, number of reference acquisitions averaged and TDC (time-to-digital converter) settings (resolution, Np multiplier (number of pushes correction factor), minimum number of points, i.e. minimum acquisition width which defines a peak). To extract the maximum information from as few experiments as possible, a Design of Experiment approach was used. The data will be used as a basis for developing guidance on accurate mass measurement on q-oaToF instruments.     

Structure and Raman spectrum of clavulanic acid in aqueous solution

The calculation of the vibrational Raman spectrum of enzyme-bound beta-lactamase inhibitors may be of help to understand the mechanisms responsible for bacterial drug resistance. Here, we present a study of the solvation structure and the vibrational properties of clavulanate, an important beta-lactamase inhibitor, in aqueous solution as obtained from full quantum and hybrid empirical/quantum molecular dynamics simulations at ambient conditions. The analysis of the vibrational density of states indicates that hybrid empirical/quantum mechanical simulations are able to properly describe the vibrational levels of clavulanate in solution. In addition, we propose a computationally efficient protocol to calculate the vibrational Raman effect for large solute molecules in water, which is able to faithfully reproduce the experimentally recorded clavulanate Raman spectrum and discloses the possibility to employ hybrid simulations to assign the experimental Raman spectra of inhibitors bound to beta-lactamases.     

Reaction of Cl with CD4 excited to the second C-D stretching overtone

The effects of vibrational excitation on the Cl+CD(4) reaction are investigated by preparing three nearly isoenergetic vibrational states: mid R:3000 at 6279.66 cm(-1), |2100> at 6534.20 cm(-1), and |1110> at 6764.24 cm(-1), where |D(1)D(2)D(3)D(4)> identifies the number of vibrational quanta in each C-D oscillator. Vibrational excitation of the perdeuteromethane is via direct infrared pumping. The reaction is initiated by photolysis of molecular chlorine at 355 nm. The nascent methyl radical product distribution is measured by 2+1 resonance-enhanced multiphoton ionization at 330 nm. The resulting CD(3) state distributions reveal a preference to remove all energy available in the most excited C-D oscillator. Although the energetics are nearly identical, the authors observe strong mode specificity in which the CD(3) state distributions markedly differ between the three Cl-atom reactions. Reaction with CD(4) prepared in the |3000> mode leads to CD(3) products populated primarily in the ground state, reaction with CD(4) prepared in the |2100> mode leads primarily to CD(3) with one quantum of stretch excitation, and reaction with CD(4) prepared in the |1110> mode leads primarily to CD(3) with one quantum of C-D stretch excitation in two oscillators. There are some minor deviations from this behavior, most notably that the Cl atom is able to abstract more energy than is available in a single C-D oscillator, as in the case of |2100>, wherein a small population of ground-state CD(3) is observed. These exceptions likely result from the mixings between different second overtone stretch combination bands. They also measure isotropic and anisotropic time-of-flight profiles of CD(3) (nu(1)=1,2) products from the Cl+CD(4) |2100> reaction, providing speed distributions, spatial anisotropies, and differential cross sections that indicate that energy introduced as vibrational energy into the system essentially remains as such throughout the course of the reaction.     

Two New Retigerane‐Type Sesterterpenoids from the Lichen Leprocaulon microscopicum

Two new sesterterpenes, 1 and 2 , have been isolated from the lichen Leprocaulon microscopicum. In addition to classic chromatographic methods, a liquid‐liquid chromatography technique, namely centrifugal partition chromatography (CPC) was applied for the purification of compound 2 . The structures were determined by analyses of mass spectrometry and 1D‐ and 2D‐NMR data. The relative configuration of the isolated compounds was assigned on the basis of 2D‐NOESY experiments. The two compounds possess a rare pentacyclic carbon skeleton typical for lichen metabolism, and quite unusual in the vegetal kingdom.     

Conformational Dynamics in the Core of Human Y145Stop Prion Protein Amyloid Probed by Relaxation Dispersion NMR

Microsecond to millisecond timescale backbone dynamics of the amyloid core residues in Y145Stop human prion protein (PrP) fibrils were investigated by using ¹⁵N rotating frame (R_1ρ) relaxation dispersion solid-state nuclear magnetic resonance spectroscopy over a wide range of spin-lock fields. Numerical simulations enabled the experimental relaxation dispersion profiles for most of the fibril core residues to be modelled by using a two-state exchange process with a common exchange rate of 1000 s⁻¹, corresponding to protein backbone motion on the timescale of 1 ms, and an excited-state population of 2 %. We also found that the relaxation dispersion profiles for several amino acids positioned near the edges of the most structured regions of the amyloid core were better modelled by assuming somewhat higher excited-state populations (∼5–15 %) and faster exchange rate constants, corresponding to protein backbone motions on the timescale of ∼100–300 μs. The slow backbone dynamics of the core residues were evaluated in the context of the structural model of human Y145Stop PrP amyloid.     

Influence of the electric field on a bio-mimetic film supported on a gold electrode

A model biological membrane was formed by fusion of mixed cholesterol and DMPC (dimyristoylphosphatidylcholine) phospholipid vesicles onto a gold-coated quartz support. The gold surface was charged and the influence of the charge at the solid support on the structure and integrity of the phospholipid bilayer was investigated using the specular reflection of neutrons and electrochemical measurements. When the surface charge density is close to zero, the lipid vesicles fuse directly on the surface to form a bilayer with a small number of defects and hence low water content. When the support's surface is negatively charged the film swells and incorporates water due to the field driven poration of the membrane. When the charge density is more negative then -8 microC cm(-2) the bilayer is detached from the metal surface. However, it remains in close proximity to the metal electrode, suspended on a thin cushion of water. The film thicknesses, calculated from neutron reflectivity, have allowed us to determine the tilt angle of the lipid molecules as a function of the support's charge density. The lipid molecules are tilted 55 degrees from the surface normal at zero charge density but become significantly more perpendicular (30 degrees tilt angle) at charge densities more negative than -8 microC cm(-2). The tilt angle measurements are in very good agreement with previous IR studies. This paper describes the highlights of a more in-depth study which is fully described in [1].     

Structure and properties of the ion pair charge-transfer complex of octacyanotungstate(IV) with the 2,2′-bipyridinium dication

The X-ray crystal structure of (bpyH2)2[W(CN)8]·4H2 O (bpyH2=2,2-bipyridinium) is described. The [W(CN)8]4– anion has an approximately square antiprismatic (D4d) conformation, seemingly imposed by strong anion–water–cation hydrogen-bonding interactions. Bond distances in the anion are: WC 2.150(5), 2.163(5); CN 1.128(6), 1.145(6)Å and the angles WCN are 177.6(5), 178.3(5)°. The dihydrate and the anhydrous salt are both intensely black solids, exhibiting ion-pair charge-transfer interaction between cation and anion. E.s.r. spectra indicate that 30% of the tungsten is present as WV in the solid state, but that in solution only the WIV complex is present. The electron withdrawing effect of the cation is discussed and compared with that in a series of salts with different bipyridinium cations.